OFQ, a heptadeca-peptide, has been isolated from rat brain and is a natural ligand to a G-protein coupled receptor (OFQ-R), found at high levels in brain tissue. OFQ exhibits agonistic activity at the OFQ-R both in vitro and in vivo.
Julius (Nature 377,476, [1995]) discusses the discovery of OFQ noting that this peptide shares greatest sequence homology with dynorphin A, an established endogenous ligand for opioid receptors. OFQ inhibits adenylate cyclase in CHO(LC 132.sup.+) cells in culture and induces hyperalgesia when administered intracerebroventricularly to mice. The pattern of results indicate that this heptadecapeptide is an endogenous agonist of the LC 132 receptor and it appears to have pronociceptive properties. It has been described that when injected intracerebroventricularly in mice, OFQ slowes down locomotive activity and induces hyperalgesia and it has been concluded that OFQ may act as a brain neurotransmitter to modulate nociceptive and locomotive behavior.
It has been found that the compounds of the present invention interact with the orphanin FQ (OFQ) receptor and consequently are useful in the treatment of a variety of psychiatric, neurological and physiological disorders.
In the following references these indications have been described:
Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor, Eur. J. Pharmacol., 340: 1-15, 1997; PA1 The orphan opioid receptor and its endofenous ligand ociceptin/orphanin FQ, Trends Pharmacol. Sci., 18:293-300, 1997; PA1 Orphanin FQ is a functional anti-opioid peptide, Neuroscience, 75:333-337, 1996; PA1 Orphanin FQ/nociceptin-lack of antinociceptive, hyperalgesic or allodynic effects in acute thermal or mechanical tests, following intracerebroventricular or intrathecal administration to mice or rats, Eur. J. pain, 2:267-280, 1998; PA1 Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress, Proc. Natl. Acad. Sci., USA, 94: 14854-14858, 1997; PA1 Orphanin FQ, an agonist of orphan opioid receptor ORL1, stimulates feeding in rats, Neuroreport, 8:369-371, 1996; PA1 Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors, Nature, 394: 577-581, 1998; PA1 Distribution of nociceptin/orphanin FQ receptor transcript in human central nervous system and immune cells, J. Neuroimmuno, 81:184-192, 1998; PA1 Orphamin FQ plays a role in sepsis, Prog. Clin. Biol. Res. (1998), 397, 315-325. PA1 R.sup.2 is .dbd.O or hydrogen, PA1 R.sup.3 is hydrogen, isoindolyl-1,3-dione, lower alkoxy, lower alkyl, amino, benzyloxy, --CH.sub.2 OR.sup.5 or --CH.sub.2 N(R.sup.5).sub.2 ; PA1 R.sup.4 is hydrogen or --CH.sub.2 OR.sup.5 ; PA1 R.sup.5 is hydrogen or lower alkyl; ##STR4## is cyclohexyl or phenyl, optionally substituted by lower alkyl, halogen or alkoxy, and to pharmaceutically acceptable acid addition salts thereof. PA1 a) reductively aminating a compound of formula ##STR5## with a compound of formula ##STR6## wherein R.sup.1, R.sup.2 R.sup.3, R.sup.4 and ##STR7## have the significances given above, or b) condensing an imine of formula ##STR8## with a carboxylic acid derivative of formula ##STR9## to a compound of formula ##STR10## wherein R.sup.1, R.sup.3, R.sup.4 and ##STR11## have the significances given above, and X is halogen, or
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable addition salts thereof, racemic mixtures and their corresponding enantiomers, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred above, or in the manufacture of corresponding medicaments.